Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over-expressed in numerous cancers, Ubiquitin-like containing PHD Ring Finger 1 (UHRF1, also known as ICBP90 or Np95) is characterized by a SRA domain (Set and Ring Associated) which is found only in the UHRF family. UHRF1 constitutes a complex with histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) via its SRA domain and represses the expression of several tumour suppressor genes (TSGs) including p16INK4A, hMLH1, BRCA1 and RB1. Conversely, UHRF1 is regulated by other TSGs such as p53 and p73. UHRF1 is hypothetically involved in a macro-molecular protein complex called "ECREM" for "Epigenetic Code Replication Machinery". This complex would be able to duplicate the epigenetic code by acting at the DNA replication fork and by activating the right enzymatic activity at the right moment. There are increasing evidence that UHRF1 is the conductor of this replication process by ensuring the crosstalk between DNA methylation and histone modifications via the SRA and Tandem Tudor Domains, respectively. This cross-talk allows cancer cells to maintain the repression of TSGs during cell proliferation. Several studies showed that down-regulation of UHRF1 expression in cancer cells by natural pharmacological active compounds, favors enhanced expression or re-expression of TSGs, suppresses cell growth and induces apoptosis. This suggests that hindering UHRF1 to exert its role in the duplication of the methylation patterns (DNA + histones) is responsible for inducing apoptosis. In this review, we present UHRF1 expression as a target of several natural products and we discuss their underlying molecular mechanisms and benefits for chemoprevention and chemotherapy.
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PMID:Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties. 2149 37

Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is an important nuclear protein that is mutated and aberrantly expressed in many tumors. The protein integrates different chromatin modifications and is essential for their maintenance throughout the cell cycle. Separate chromatin-binding modules of UHRF1 have been studied on a functional and structural level. The unmodified N-terminus of histone H3 is recognized by a PHD domain, while a TTD domain specifically interacts with histone H3 Lysine 9 trimethylation. A SRA region binds hemimethylatd DNA. Emerging evidence indicates that the modules of UHRF1 do not act independently of each other but establish complex modes of interaction with patterns of chromatin modifications. This multivalent readout is regulated by allosteric binding of phosphatidylinositol 5-phosphate to a region outside the PHD, TTD and SRA domains as well as by phosphorylation of one of the linker regions connecting these modules. Here, we summarize the current knowledge on UHRF1 chromatin interaction and introduce a novel model of conformational transitions of the protein that are directed by the flexible and highly charged linker regions. We propose that these are essential in setting up defined structural states of the protein where different domains or combinations thereof are available for binding chromatin modifications or are prevented from doing so. Lastly, we suggest that controlled tuning of intramolecular linker interactions by ligands and posttranslational modifications establishes a rational framework for comprehending UHRF1 regulation and putatively the working mode of other chromatin factors in different physiological contexts.
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PMID:Conserved linker regions and their regulation determine multiple chromatin-binding modes of UHRF1. 2589 92

Ubiquitin-like containing PHD Ring Finger 1 (UHRF1) is a multi-domain protein with a methyl-DNA binding SRA (SET and RING-associated) domain, required for maintenance DNA methylation mediated by DNMT1. Primarily expressed in proliferating cells, UHRF1 is a cell-cycle regulated protein that is required for S phase entry. Furthermore, UHRF1 participates in transcriptional gene regulation by connecting DNA methylation to histone modifications. Upregulation of UHRF1 may serve as a biomarker for a variety of cancers; including breast, gastric, prostate, lung and colorectal carcinoma. To this end, overexpression of UHRF1 promotes cancer metastasis by triggering aberrant patterns of DNA methylation, and subsequently, silencing tumor suppressor genes. Various small molecule effectors of UHRF1 have been reported in the literature, although the mechanism of action may not be fully characterized. Small molecules that potentially bind to the SRA domain may affect the ability of UHRF1 to bind hemimethylated DNA; thereby reducing aberrant DNA methylation. Therefore, in a subset of cancers, small molecule UHRF1 inhibitors may restore normal gene expression and serve as useful anti-cancer therapeutics.
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PMID:Targeting the SET and RING-associated (SRA) domain of ubiquitin-like, PHD and ring finger-containing 1 (UHRF1) for anti-cancer drug development. 2989 56

The figure describes the location of UHRF1 (Ubiquitin-like with containing PHD and RING Finger domains 1) gene, mRNA and protein synthesis in the tumor cell and its structural domains with a focus on the docking of Naphthazarin on the SRA domain of UHRF1, resulting in reduction of tumor size.
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PMID:Role of UHRF1 in malignancy and its function as a therapeutic target for molecular docking towards the SRA domain. 3139 Nov 49

Cancer pathogenesis has been attributed to the minor and major disruptions in the cell cycle, with a key role being played by several of the recently discovered epigenetic factors. Lately, UHRF1 (Ubiquitin-like with containing PHD and RING Finger domains 1), an epigenetic regulator has been shown to be evidently over expressed in numerous malignancies through an in-depth review of literature. Molecular docking studies have found that existing drugs such as propranolol, naphthazarin and thymoquinone have favourable interactions with specific domains of UHRF1. However, these findings would need large scale clinical trials to confirm their potency and safety during chemotherapy. UHRF1 (Ubiquitin-like with containing PHD and RING Finger domains 1), an epigenetic factor, plays a crucial role as an important checkpoint in the cell machinery. Basic science continues to unravel multiple facets of this five domain protein which includes a detailed elucidation of its roles and mechanisms of interaction with various enzymes during DNA replication. The gene has recently begun to be also termed as the "Universal Oncogene" in response to the results of research conducted in heterogenous populations and in over 17 cancers displaying heightened mRNA and protein expression in breast, liver, lung, head and neck cancers and many more. This gene could therefore, be a potential biomarker for diagnosis and for the prediction of the prognosis and survival of the diseased. A scientifically established solution in the form of targeted treatment must follow such a discovery and therefore, several natural and synthetic compounds such as thymoquinone and the well-known antihypertensive, propranolol have been docked and reported to have favourable interactions with the SRA (Set and Ring Associated) domain of UHRF1 in this review. This comprehensive review is thus, a brief synopsis of details regarding the structure and heightened levels of UHRF1 in several malignancies. Furthermore, pharmacogenomic research revolving around this oncogene is a potential sphere for clinical studies to be conducted in much larger and heterogenous populations to not only validate these therapeutic docking results but to also to bring personalised medicine to the bedside for the benefit of the patients.
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PMID:Corrigendum to "Role of UHRF1 in malignancy and its function as a therapeutic target for molecular docking towards the SRA domain" [Int. J. Biochem. Cell Biol. 114 (September 2019) 105558]. 3123 11